JP5277837B2 - Process for producing α-trifluoromethyl-α, β-unsaturated esters - Google Patents
Process for producing α-trifluoromethyl-α, β-unsaturated esters Download PDFInfo
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- JP5277837B2 JP5277837B2 JP2008247053A JP2008247053A JP5277837B2 JP 5277837 B2 JP5277837 B2 JP 5277837B2 JP 2008247053 A JP2008247053 A JP 2008247053A JP 2008247053 A JP2008247053 A JP 2008247053A JP 5277837 B2 JP5277837 B2 JP 5277837B2
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- Prior art keywords
- group
- substituted
- trifluoromethyl
- alkyl group
- general formula
- Prior art date
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- 150000002148 esters Chemical class 0.000 title claims description 33
- 238000000034 method Methods 0.000 title claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 150000007530 organic bases Chemical class 0.000 claims description 22
- 239000005935 Sulfuryl fluoride Substances 0.000 claims description 21
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 9
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 9
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical group C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000758 substrate Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 238000004817 gas chromatography Methods 0.000 description 16
- 239000002994 raw material Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 10
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 230000001012 protector Effects 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- -1 propylthio group Chemical group 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 239000012925 reference material Substances 0.000 description 7
- 239000003507 refrigerant Substances 0.000 description 7
- 229910001220 stainless steel Inorganic materials 0.000 description 7
- 239000010935 stainless steel Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 125000003172 aldehyde group Chemical group 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 239000011903 deuterated solvents Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 description 5
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000003905 agrochemical Substances 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 239000012024 dehydrating agents Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 238000005055 short column chromatography Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- ISNICOKBNZOJQG-UHFFFAOYSA-N 1,1,2,3,3-pentamethylguanidine Chemical compound CN=C(N(C)C)N(C)C ISNICOKBNZOJQG-UHFFFAOYSA-N 0.000 description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 description 2
- NURQLCJSMXZBPC-UHFFFAOYSA-N 3,4-dimethylpyridine Chemical compound CC1=CC=NC=C1C NURQLCJSMXZBPC-UHFFFAOYSA-N 0.000 description 2
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000002316 fumigant Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- NSRBCQCXZAYQHF-UHFFFAOYSA-N n-[[tert-butylimino-bis[[tris(dimethylamino)-$l^{5}-phosphanylidene]amino]-$l^{5}-phosphanyl]imino-bis(dimethylamino)-$l^{5}-phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)(N(C)C)=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C NSRBCQCXZAYQHF-UHFFFAOYSA-N 0.000 description 2
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910004261 CaF 2 Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000006015 bromomethoxy group Chemical group 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004651 chloromethoxy group Chemical group ClCO* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000010436 fluorite Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Chemical group 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- SLVAEVYIJHDKRO-UHFFFAOYSA-N trifluoromethanesulfonyl fluoride Chemical compound FC(F)(F)S(F)(=O)=O SLVAEVYIJHDKRO-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C67/327—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by elimination of functional groups containing oxygen only in singly bound form
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、医農薬中間体として重要なα−トリフルオロメチル−α,β−不飽和エステル類の製造方法に関する。 The present invention relates to a process for producing α-trifluoromethyl-α, β-unsaturated esters important as intermediates for pharmaceuticals and agricultural chemicals.
α−トリフルオロメチル−α,β−不飽和エステル類は、医農薬中間体として重要である。本発明に関連する製造技術として、脱水剤に塩化チオニル(SOCl2)、五酸化二燐(P2O5)、無水酢酸[(CH3CO)2O]またはトリフルオロメタンスルホン酸無水物[(CF3SO2)2O]を用いる例が報告されている(非特許文献1から6、特許文献1)。その中でもトリフルオロメタンスルホン酸無水物による方法は、β位プロトンの酸性度が低い(所望の反応が進行し難い)原料基質にも適応できるため、最も優れた方法と考えられる。 α-Trifluoromethyl-α, β-unsaturated esters are important as pharmaceutical and agrochemical intermediates. Production techniques related to the present invention include thionyl chloride (SOCl 2 ), diphosphorus pentoxide (P 2 O 5 ), acetic anhydride [(CH 3 CO) 2 O] or trifluoromethanesulfonic anhydride [( Examples using CF 3 SO 2 ) 2 O] have been reported (Non-Patent Documents 1 to 6, Patent Document 1). Among them, the method using trifluoromethanesulfonic anhydride is considered the most excellent method because it can be applied to a raw material substrate in which the acidity of the β-position proton is low (desired reaction does not proceed easily).
本出願人は、スルフリルフルオリド(SO2F2)と有機塩基の組み合わせによるアルコール類の脱ヒドロキシフッ素化反応を開示している(特許文献2)。
本発明の目的は、α−トリフルオロメチル−α,β−不飽和エステル類の実用的な製造方法を提供することにある。そのためには、従来技術の問題点を解決する必要がある。 An object of the present invention is to provide a practical method for producing α-trifluoromethyl-α, β-unsaturated esters. For that purpose, it is necessary to solve the problems of the prior art.
非特許文献1から6に対しては、隣接する電子求引基によりβ位プロトンの酸性度が高い原料基質や、中間体の脱離基(原料基質のヒドロキシル基から誘導された)が共役系の電子押し出しにより脱離し易い場合に限定され、基質適応範囲が非常に狭い。 For Non-Patent Documents 1 to 6, a raw material substrate having high β-position proton acidity due to an adjacent electron-withdrawing group and an intermediate leaving group (derived from the hydroxyl group of the raw material substrate) are conjugated. It is limited to the case where it can be easily detached by electron extrusion, and the substrate application range is very narrow.
特許文献1に対しては、広範な基質適応範囲が謳われているが、本発明の原料基質であるα−トリフルオロメチル−α−ヒドロキシエステル類を用いた場合の具体的な反応条件(代表例と同様に行うとのみ記載)や収率が開示されていない。そこで該特許文献における好適な反応条件(脱水剤;トリフルオロメタンスルホン酸無水物、塩基;ピリジン、反応溶媒;塩化メチレン、温度条件;0から35℃)を採用して、本発明で対象とするα−トリフルオロメチル−α−ヒドロキシエステル類の脱水反応を追試したところ、収率が極めて低いことが判明した(後述の表−2の比較例1および表−3の比較例4を参照)。低収率の原因は中間体から目的生成物への脱離速度が極めて遅いことに起因しており、α−トリフルオロメチル−α,β−不飽和エステル類の実用的な製造方法とは言い難いものであった(スキーム1を参照)。 For Patent Document 1, a wide range of substrate application is envisaged, but specific reaction conditions (representative) when α-trifluoromethyl-α-hydroxyesters, which are raw material substrates of the present invention, are used. Only described in the same manner as in the examples) and yields are not disclosed. Therefore, by adopting suitable reaction conditions (dehydrating agent; trifluoromethanesulfonic anhydride, base; pyridine, reaction solvent; methylene chloride, temperature condition; 0 to 35 ° C.) in the patent document, α targeted by the present invention When the dehydration reaction of -trifluoromethyl-α-hydroxyesters was further tried, it was found that the yield was extremely low (see Comparative Example 1 in Table 2 and Comparative Example 4 in Table 3 described later). The reason for the low yield is that the elimination rate from the intermediate to the target product is extremely slow, which is a practical method for producing α-trifluoromethyl-α, β-unsaturated esters. It was difficult (see Scheme 1).
また、トリフルオロメタンスルホン酸無水物はトリフルオロメタンスルホニル(CF3SO2)基を2つ有するが、中間体の脱離基への誘導にはその内の1つが利用されるだけであり、アトムエコノミーの観点からも好ましい脱水剤とは言えない。さらに、目的生成物1分子に対して、難分解性で廃棄に問題のあるトリフルオロメタンスルホン酸(CF3SO3H)を2分子の割合で副生するため、大量規模での生産に適した製造方法とも言えない。 In addition, trifluoromethanesulfonic anhydride has two trifluoromethanesulfonyl (CF 3 SO 2 ) groups, but only one of them is used to derive the intermediate leaving group, and the atom economy From this point of view, it is not a preferable dehydrating agent. Furthermore, trifluoromethanesulfonic acid (CF 3 SO 3 H), which is difficult to decompose and has a problem with disposal, is produced as a by-product at a ratio of 2 molecules per molecule of target product, making it suitable for large-scale production. It cannot be said to be a manufacturing method.
この様に、基質適応範囲が広く、短時間で収率良く(生産性が高く)、反応剤のアトムエコノミーが高く廃棄物処理も問題とならない、実用的な製造方法が強く望まれていた。 Thus, there has been a strong demand for a practical production method that has a wide substrate application range, a high yield in a short time (high productivity), a high atom economy of the reactants, and no waste disposal problems.
本発明者らは、上記の課題を踏まえて鋭意検討した結果、α−トリフルオロメチル−α−ヒドロキシエステル類を有機塩基の存在下にスルフリルフルオリドと反応させることにより、α−トリフルオロメチル−α,β−不飽和エステル類が製造できることを見出した。また、原料基質としては、β位置換基の片方が水素原子であり、他方がアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基であり、さらにエステル基がアルキルエステルである場合がより好ましいことも明らかにした。該原料基質は入手が容易であり、所望の反応が良好に進行し、得られるα−トリフルオロメチル−α,β−不飽和エステル類も医農薬中間体として特に重要である。さらに、有機塩基としては、1,5−ジアザビシクロ[4.3.0]ノン−5−エン(DBN)または1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)がより好ましいことも明らかにした。該有機塩基を用いることにより、所望の反応がさらに良好に進行する。 As a result of intensive studies based on the above-mentioned problems, the present inventors have reacted α-trifluoromethyl-α-hydroxyesters with sulfuryl fluoride in the presence of an organic base to produce α-trifluoromethyl- It has been found that α, β-unsaturated esters can be produced. As the raw material substrate, one of the β-position substituents is a hydrogen atom, the other is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group, and an ester group It was also clarified that the alkyl ester is more preferable. The raw material substrate is easily available, the desired reaction proceeds well, and the α-trifluoromethyl-α, β-unsaturated esters obtained are particularly important as intermediates for medicines and agrochemicals. Further, the organic base is 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). It was also revealed that it was preferable. By using the organic base, the desired reaction proceeds even better.
本発明の製造条件は、特許文献2で開示した脱ヒドロキシフッ素化反応の条件に類似するものであり、実際にα位ヒドロキシル基がフッ素原子に置換したフッ素化物も副生する[スキーム−1(実施例1)を参照]。しかしながら、本発明の原料基質であるα−トリフルオロメチル−α−ヒドロキシエステル類を用いると、脱水体であるα−トリフルオロメチル−α,β−不飽和エステル類が選択的に得られることを見出した。 The production conditions of the present invention are similar to the dehydroxyfluorination reaction conditions disclosed in Patent Document 2, and a fluorinated product in which the α-position hydroxyl group is actually substituted with a fluorine atom is also produced as a by-product [Scheme-1 ( See Example 1)]. However, when α-trifluoromethyl-α-hydroxyesters which are raw material substrates of the present invention are used, α-trifluoromethyl-α, β-unsaturated esters which are dehydrates can be selectively obtained. I found it.
また、反応剤としては、同様の効果が期待されるトリフルオロメタンスルホニルフルオリド(CF3SO2F)に比べてスルフリルフルオリドが変換率やGC純度において格段に優れていることも明らかにした(表−1の比較例2と実施例2の比較、および比較例3と実施例3の比較)。 In addition, as a reactant, it has also been clarified that sulfuryl fluoride is remarkably superior in conversion and GC purity compared to trifluoromethanesulfonyl fluoride (CF 3 SO 2 F), which is expected to have the same effect ( Comparison of Comparative Example 2 and Example 2 in Table 1 and Comparison of Comparative Example 3 and Example 3).
さらに、有機塩基としては、トリエチルアミンでも所望の反応は良好に進行するが、1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エンの方がGC純度において優れており(表−1の実施例2と実施例3の比較、および表−2の実施例4と実施例5の比較)、トリエチルアミンよりも塩基性の強い有機塩基{具体的には、1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン以外に、4−ジメチルアミノピリジン(DMAP)、1,5−ジアザビシクロ[4.3.0]ノン−5−エン(DBN)、N,N,N’,N’,N’’−ペンタメチルグアニジン、1,5,7−トリアザビシクロ[4.4.0]デセ−5−エン(TBD)、BEMPおよびt−Bu−P4等のホスファゼンベース等}がより好ましいことも明らかにした。 Furthermore, although the desired reaction proceeds well even with triethylamine as the organic base, 1,8-diazabicyclo [5.4.0] undec-7-ene is superior in GC purity (Table 1). Comparison between Example 2 and Example 3 and comparison between Example 4 and Example 5 in Table 2), an organic base having a stronger basicity than triethylamine {specifically, 1,8-diazabicyclo [5.4 .0] Undec-7-ene, 4-dimethylaminopyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), N, N, N ′, N ′ , N ″ -pentamethylguanidine, 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD), BEMP, phosphazene bases such as t-Bu-P4, etc.} Also revealed that it is preferable
この様に、α−トリフルオロメチル−α,β−不飽和エステル類の製造方法として極めて有用な方法を見出し、本発明に到達した。 Thus, a very useful method was found as a method for producing α-trifluoromethyl-α, β-unsaturated esters, and the present invention was achieved.
すなわち、本発明は[発明1]から[発明3]を含み、α−トリフルオロメチル−α,β−不飽和エステル類の実用的な製造方法を提供する。 That is, the present invention includes [Invention 1] to [Invention 3] and provides a practical method for producing α-trifluoromethyl-α, β-unsaturated esters.
[発明1]
一般式[1]
[Invention 1]
General formula [1]
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類を有機塩基の存在下にスルフリルフルオリド(SO2F2)と反応させることにより、一般式[2] Is reacted with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base to give a general formula [2]
で示されるα−トリフルオロメチル−α,β−不飽和エステル類を製造する方法。
[式中、R1およびR2はそれぞれ独立に水素原子、アルキル基、置換アルキル基、アルケニル基、置換アルケニル基、アルキニル基、置換アルキニル基、芳香環基、置換芳香環基、アルキルカルボニル基、置換アルキルカルボニル基、アルコキシカルボニル基、置換アルコキシカルボニル基、アリールカルボニル基、置換アリールカルボニル基、シアノ基またはニトロ基を表し、R3はアルキル基または置換アルキル基を表す。一般式[2]の波線は、二重結合の立体化学がE体、Z体、またはE体とZ体の混合物であることを表す]
[発明2]
一般式[3]
A method for producing an α-trifluoromethyl-α, β-unsaturated ester represented by the formula:
Wherein R 1 and R 2 are each independently a hydrogen atom, alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, aromatic ring group, substituted aromatic ring group, alkylcarbonyl group, A substituted alkylcarbonyl group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an arylcarbonyl group, a substituted arylcarbonyl group, a cyano group or a nitro group is represented, and R 3 represents an alkyl group or a substituted alkyl group. The wavy line of general formula [2] indicates that the stereochemistry of the double bond is E-form, Z-form, or a mixture of E-form and Z-form]
[Invention 2]
General formula [3]
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類を有機塩基の存在下にスルフリルフルオリド(SO2F2)と反応させることにより、一般式[4] Is reacted with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base to give a general formula [4]
で示されるα−トリフルオロメチル−α,β−不飽和エステル類を製造する方法。
[式中、R4はアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基を表し、R5はアルキル基を表す。一般式[4]の波線は、二重結合の立体化学がE体、Z体、またはE体とZ体の混合物であることを表す]
[発明3]
発明1または発明2において、有機塩基が1,5−ジアザビシクロ[4.3.0]ノン−5−エン(DBN)または1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)であることを特徴とする、発明1または発明2に記載のα−トリフルオロメチル−α,β−不飽和エステル類の製造方法。
A method for producing an α-trifluoromethyl-α, β-unsaturated ester represented by the formula:
[Wherein, R 4 represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group, and R 5 represents an alkyl group. The wavy line in the general formula [4] indicates that the stereochemistry of the double bond is E-form, Z-form, or a mixture of E-form and Z-form]
[Invention 3]
In invention 1 or invention 2, the organic base is 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The method for producing α-trifluoromethyl-α, β-unsaturated esters according to Invention 1 or Invention 2, characterized in that:
本発明が従来技術に比べて有利な点を以下に述べる。 The advantages of the present invention over the prior art will be described below.
本発明の製造方法は、基質適応範囲が広く、目的物を高い生産性で収率良く得ることができる。さらに、分離の難しい不純物を殆ど副生しないため、目的物を高い化学純度で得ることができる。本発明で用いるスルフリルフルオリドは、アトムエコノミーが高く、廃棄物処理においても蛍石(CaF2)や硫酸カルシウム(CaSO4)等の、特に問題とならない無機塩に簡便に処理することができる。また、スルフリルフルオリドは燻蒸剤として広く利用されており、特許文献1で開示されたトリフルオロメタンスルホン酸無水物やフルオロ硫酸無水物[(FSO2)2O]等の脱水剤に比べて大量に且つ安価に入手することができる。 The production method of the present invention has a wide substrate application range and can obtain the target product with high productivity and high yield. Furthermore, since hardly separated impurities are hardly produced as a by-product, the target product can be obtained with high chemical purity. The sulfuryl fluoride used in the present invention has a high atom economy, and can be easily treated with inorganic salts such as fluorite (CaF 2 ) and calcium sulfate (CaSO 4 ) that are not particularly problematic in waste treatment. In addition, sulfuryl fluoride is widely used as a fumigant, and in a larger amount than a dehydrating agent such as trifluoromethanesulfonic anhydride or fluorosulfuric anhydride [(FSO 2 ) 2 O] disclosed in Patent Document 1. And it can be obtained at a low cost.
この様に、本発明は従来技術の問題点を全て解決し、工業的にも実施可能な製造方法である。最後に、燻蒸剤であるスルフリルフルオリドを有機合成において脱水剤として使用した例は、本発明者らの知る限りにおいては報告されていない。 Thus, the present invention solves all the problems of the prior art and is a manufacturing method that can be implemented industrially. Finally, to the best of our knowledge, no report has been made of the use of sulfuryl fluoride, a fumigant, as a dehydrating agent in organic synthesis.
本発明のα−トリフルオロメチル−α,β−不飽和エステル類の製造方法について詳細に説明する。 The method for producing α-trifluoromethyl-α, β-unsaturated esters of the present invention will be described in detail.
本発明は、一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類を有機塩基の存在下にスルフリルフルオリドと反応させることにより、一般式[2]で示されるα−トリフルオロメチル−α,β−不飽和エステル類を製造する方法である。 In the present invention, α-trifluoromethyl-α-hydroxyesters represented by the general formula [1] are reacted with sulfuryl fluoride in the presence of an organic base to produce α-trimethyl represented by the general formula [2]. This is a method for producing fluoromethyl-α, β-unsaturated esters.
一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類のR1およびR2は、それぞれ独立に水素原子、アルキル基、置換アルキル基、アルケニル基、置換アルケニル基、アルキニル基、置換アルキニル基、芳香環基、置換芳香環基、アルキルカルボニル基、置換アルキルカルボニル基、アルコキシカルボニル基、置換アルコキシカルボニル基、アリールカルボニル基、置換アリールカルボニル基、シアノ基またはニトロ基を表す。その中でもそれぞれ独立に水素原子、アルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基および置換芳香環基が好ましく、特に片方が水素原子であり、他方がアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基および置換芳香環基がより好ましい。 R 1 and R 2 of the α-trifluoromethyl-α-hydroxyester represented by the general formula [1] are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, It represents a substituted alkynyl group, aromatic ring group, substituted aromatic ring group, alkylcarbonyl group, substituted alkylcarbonyl group, alkoxycarbonyl group, substituted alkoxycarbonyl group, arylcarbonyl group, substituted arylcarbonyl group, cyano group or nitro group. Among them, a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group, and a substituted aromatic ring group are preferable, particularly one is a hydrogen atom, and the other is an alkyl group, a substituted alkyl group, An alkenyl group, a substituted alkenyl group, an aromatic ring group, and a substituted aromatic ring group are more preferable.
アルキル基は、炭素数が1から18の、直鎖または枝分れの鎖式、または環式(炭素数が3以上の場合)を採ることができる。アルケニル基は、上記のアルキル基の、任意の隣り合う2つの炭素原子の単結合が二重結合に、任意の数で置き換わり、該二重結合の立体化学はE体、Z体、またはE体とZ体の混合物を採ることができる。アルキニル基は、上記のアルキル基の、任意の隣り合う2つの炭素原子の単結合が三重結合に、任意の数で置き換わることができる。芳香環基は、炭素数が1から18の、フェニル基、ナフチル基、アントリル基等の芳香族炭化水素基、またはピロリル基、フリル基、チエニル基、インドリル基、ベンゾフリル基、ベンゾチエニル基等の窒素原子、酸素原子または硫黄原子等のヘテロ原子を含む芳香族複素環基を採ることができる。アルキルカルボニル基(−COR)のアルキル基(R)は、上記のアルキル基と同じである。アルコキシカルボニル基(−CO2R)のアルキル基(R)は、上記のアルキル基と同じである。アリールカルボニル基(−COAr)のアリール基(Ar)は、上記の芳香環基と同じである。 The alkyl group can have a straight chain or branched chain structure having 1 to 18 carbon atoms, or a cyclic structure (when the number of carbon atoms is 3 or more). In the alkenyl group, a single bond of any two adjacent carbon atoms in the above alkyl group is replaced with a double bond in any number, and the stereochemistry of the double bond is E-form, Z-form, or E-form. And a Z-form mixture can be taken. In the alkynyl group, a single bond of any two adjacent carbon atoms in the above alkyl group can be replaced with a triple bond in any number. The aromatic ring group is an aromatic hydrocarbon group having 1 to 18 carbon atoms, such as a phenyl group, a naphthyl group, an anthryl group, or a pyrrolyl group, a furyl group, a thienyl group, an indolyl group, a benzofuryl group, a benzothienyl group, etc. An aromatic heterocyclic group containing a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom can be employed. The alkyl group (R) of the alkylcarbonyl group (—COR) is the same as the above alkyl group. The alkyl group (R) of the alkoxycarbonyl group (—CO 2 R) is the same as the above alkyl group. The aryl group (Ar) of the arylcarbonyl group (—COAr) is the same as the above aromatic ring group.
該アルキル基、アルケニル基、アルキニル基、芳香環基、アルキルカルボニル基、アルコキシカルボニル基およびアリールカルボニル基は、任意の炭素原子上に、任意の数でさらに任意の組み合わせで、置換基を有することもできる(それぞれ置換アルキル基、置換アルケニル基、置換アルキニル基、置換芳香環基、置換アルキルカルボニル基、置換アルコキシカルボニル基および置換アリールカルボニル基に対応する)。係る置換基としては、フッ素、塩素、臭素、ヨウ素のハロゲン原子、アジド基、ニトロ基、メチル基、エチル基、プロピル基等の低級アルキル基、フルオロメチル基、クロロメチル基、ブロモメチル基等の低級ハロアルキル基、メトキシ基、エトキシ基、プロポキシ基等の低級アルコキシ基、フルオロメトキシ基、クロロメトキシ基、ブロモメトキシ基等の低級ハロアルコキシ基、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基等の低級アルキルアミノ基、メチルチオ基、エチルチオ基、プロピルチオ基等の低級アルキルチオ基、シアノ基、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基等の低級アルコキシカルボニル基、アミノカルボニル基(CONH2)、ジメチルアミノカルボニル基、ジエチルアミノカルボニル基、ジプロピルアミノカルボニル基等の低級アミノカルボニル基、アルケニル基、アルキニル基等の不飽和基、フェニル基、ナフチル基、ピロリル基、フリル基、チエニル基等の芳香環基、フェノキシ基、ナフトキシ基、ピロリルオキシ基、フリルオキシ基、チエニルオキシ基等の芳香環オキシ基、ピペリジル基、ピペリジノ基、モルホリニル基等の脂肪族複素環基、ヒドロキシル基、ヒドロキシル基の保護体、アミノ基(アミノ酸またはペプチド残基も含む)、アミノ基の保護体、チオール基、チオール基の保護体、アルデヒド基、アルデヒド基の保護体、カルボキシル基、カルボキシル基の保護体等が挙げられる。なお、本明細書において、次の各用語は、それぞれ次に掲げる意味で用いられる。“低級”とは、炭素数が1から6の、直鎖または枝分れの鎖式、または環式(炭素数が3以上の場合)を意味する。“不飽和基”が二重結合の場合(アルケニル基)は、E体またはZ体の両方の幾何異性を採ることができる。“ヒドロキシル基、アミノ基、チオール基、アルデヒド基およびカルボキシル基の保護基”としては、Protective Groups in Organic Synthesis,Third Edition,1999,John Wiley & Sons,Inc.に記載された保護基等を用いることができる(2つ以上の官能基を1つの保護基で保護することもできる)。また、“不飽和基”、“芳香環基”、“芳香環オキシ基”および“脂肪族複素環基”には、ハロゲン原子、アジド基、ニトロ基、低級アルキル基、低級ハロアルキル基、低級アルコキシ基、低級ハロアルコキシ基、低級アルキルアミノ基、低級アルキルチオ基、シアノ基、低級アルコキシカルボニル基、アミノカルボニル基、低級アミノカルボニル基、ヒドロキシル基、ヒドロキシル基の保護体、アミノ基、アミノ基の保護体、チオール基、チオール基の保護体、アルデヒド基、アルデヒド基の保護体、カルボキシル基、カルボキシル基の保護体等が置換することもできる。これらの置換基の中には、有機塩基の存在下にスルフリルフルオリドと反応するものも含まれているが、好適な反応条件を採用することにより所望の反応を良好に行うことができる。 The alkyl group, alkenyl group, alkynyl group, aromatic ring group, alkylcarbonyl group, alkoxycarbonyl group and arylcarbonyl group may have a substituent on any carbon atom in any number and in any combination. (Corresponding to a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted aromatic ring group, a substituted alkylcarbonyl group, a substituted alkoxycarbonyl group and a substituted arylcarbonyl group, respectively). Examples of such substituents include fluorine, chlorine, bromine, iodine halogen atoms, azide groups, nitro groups, methyl groups, ethyl groups, propyl groups and other lower alkyl groups, fluoromethyl groups, chloromethyl groups, bromomethyl groups and other lower groups. Lower alkyl groups such as haloalkyl groups, methoxy groups, ethoxy groups, propoxy groups, etc., lower haloalkoxy groups such as fluoromethoxy groups, chloromethoxy groups, bromomethoxy groups, dimethylamino groups, diethylamino groups, dipropylamino groups, etc. Lower alkylthio groups such as amino group, methylthio group, ethylthio group and propylthio group, lower alkoxycarbonyl groups such as cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, aminocarbonyl group (CONH 2 ), dimethylaminocarbonyl group , Diethyl Lower aminocarbonyl group such as minocarbonyl group, dipropylaminocarbonyl group, unsaturated group such as alkenyl group, alkynyl group, aromatic ring group such as phenyl group, naphthyl group, pyrrolyl group, furyl group, thienyl group, phenoxy group, Aromatic ring oxy group such as naphthoxy group, pyrrolyloxy group, furyloxy group, thienyloxy group, aliphatic heterocyclic group such as piperidyl group, piperidino group, morpholinyl group, hydroxyl group, protected hydroxyl group, amino group (amino acid or Peptide group residues), amino group protectors, thiol groups, thiol group protectors, aldehyde groups, aldehyde group protectors, carboxyl groups, carboxyl group protectors, and the like. In the present specification, the following terms are used in the following meanings. “Lower” means a linear or branched chain or cyclic group having 1 to 6 carbon atoms (when the number of carbon atoms is 3 or more). When the “unsaturated group” is a double bond (alkenyl group), both E-form and Z-form geometric isomerism can be adopted. “Protecting groups for hydroxyl group, amino group, thiol group, aldehyde group and carboxyl group” are described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. Can be used (two or more functional groups can be protected with one protecting group). “Unsaturated group”, “aromatic ring group”, “aromatic ring oxy group” and “aliphatic heterocyclic group” include halogen atom, azide group, nitro group, lower alkyl group, lower haloalkyl group, lower alkoxy group. Group, lower haloalkoxy group, lower alkylamino group, lower alkylthio group, cyano group, lower alkoxycarbonyl group, aminocarbonyl group, lower aminocarbonyl group, hydroxyl group, hydroxyl group protector, amino group, amino group protector Thiol group, thiol group protector, aldehyde group, aldehyde group protector, carboxyl group, carboxyl group protector and the like can be substituted. Some of these substituents react with sulfuryl fluoride in the presence of an organic base, but a desired reaction can be favorably performed by employing suitable reaction conditions.
一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類のR3は、アルキル基または置換アルキル基を表す。その中でもアルキル基が好ましく、特に低級アルキル基がより好ましい。 R 3 of the α-trifluoromethyl-α-hydroxyester represented by the general formula [1] represents an alkyl group or a substituted alkyl group. Of these, an alkyl group is preferable, and a lower alkyl group is more preferable.
アルキル基および置換アルキル基は、上記のR1およびR2の、アルキル基および置換アルキル基と同じである。 The alkyl group and the substituted alkyl group are the same as the alkyl group and the substituted alkyl group of R 1 and R 2 described above.
一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類は、Tetrahedron(英国),2002年,第58巻,p.8565−8571およびTetrahedron Letters(英国),2004年,第45巻,p.183−185等を参考にして製造することができる。 Α-Trifluoromethyl-α-hydroxyesters represented by the general formula [1] are described in Tetrahedron (UK), 2002, Vol. 58, p. 8565-8571 and Tetrahedron Letters (UK), 2004, 45, p. It can be produced with reference to 183-185 and the like.
スルフリルフルオリドの使用量は、一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類1モルに対して0.7モル以上を用いれば良く、通常は0.8から10モルが好ましく、特に0.9から5モルがより好ましい。 The amount of sulfuryl fluoride used may be 0.7 mol or more per 1 mol of α-trifluoromethyl-α-hydroxyester represented by the general formula [1], and usually 0.8 to 10 mol. In particular, 0.9 to 5 mol is more preferable.
有機塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、トリn−プロピルアミン、トリn−ブチルアミン、トリn−ペンチルアミン、ピリジン、2,3−ルチジン、2,4−ルチジン、2,6−ルチジン、3,4−ルチジン、3,5−ルチジン、2,4,6−コリジン、3,5,6−コリジン、4−ジメチルアミノピリジン、1,5−ジアザビシクロ[4.3.0]ノン−5−エン、1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン、N,N,N’,N’,N’’−ペンタメチルグアニジン、1,5,7−トリアザビシクロ[4.4.0]デセ−5−エン、BEMPおよびt−Bu−P4等のホスファゼンベース等が挙げられる。その中でもトリエチルアミン、ジイソプロピルエチルアミン、トリn−ブチルアミン、ピリジン、2,6−ルチジン、2,4,6−コリジン、4−ジメチルアミノピリジン、1,5−ジアザビシクロ[4.3.0]ノン−5−エンおよび1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エンが好ましく、特にトリエチルアミン、ジイソプロピルエチルアミン、1,5−ジアザビシクロ[4.3.0]ノン−5−エンおよび1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エンがより好ましい。これらの有機塩基は単独または組み合わせて用いることができる。 Examples of the organic base include triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4 -Lutidine, 3,5-lutidine, 2,4,6-collidine, 3,5,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1 , 8-diazabicyclo [5.4.0] undec-7-ene, N, N, N ′, N ′, N ″ -pentamethylguanidine, 1,5,7-triazabicyclo [4.4.0 And phosphazene bases such as dece-5-ene, BEMP and t-Bu-P4. Among them, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5 Ene and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred, especially triethylamine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8- Diazabicyclo [5.4.0] undec-7-ene is more preferred. These organic bases can be used alone or in combination.
有機塩基の使用量は、一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類1モルに対して0.7モル以上を用いれば良く、通常は0.8から10モルが好ましく、特に0.9から5モルがより好ましい。有機塩基を組み合わせて用いる場合は、トータル使用量を意味し、塩基性の強い方を触媒的に用いることもできる(実施例5から7を参照)。 The organic base may be used in an amount of 0.7 mol or more with respect to 1 mol of the α-trifluoromethyl-α-hydroxyester represented by the general formula [1]. Particularly preferred is 0.9 to 5 moles. In the case of using a combination of organic bases, it means the total amount used, and the more basic one can be used catalytically (see Examples 5 to 7).
反応溶媒としては、n−ヘキサン、シクロヘキサン、n−ヘプタン等の脂肪族炭化水素系、ベンゼン、トルエン、キシレン等の芳香族炭化水素系、塩化メチレン、クロロホルム、1,2−ジクロロエタン等のハロゲン化炭化水素系、ジエチルエーテル、テトラヒドロフラン、ジイソプロピルエーテル、tert−ブチルメチルエーテル等のエーテル系、酢酸エチル、酢酸n−ブチル等のエステル系、アセトニトリル、プロピオニトリル等のニトリル系、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、1,3−ジメチル−2−イミダゾリジノン等のアミド系、ジメチルスルホキシド等が挙げられる。その中でもn−ヘキサン、n−ヘプタン、トルエン、キシレン、塩化メチレン、テトラヒドロフラン、ジイソプロピルエーテル、tert−ブチルメチルエーテル、酢酸エチル、アセトニトリル、プロピオニトリル、N,N−ジメチルホルムアミドおよびジメチルスルホキシドが好ましく、特にn−ヘプタン、トルエン、塩化メチレン、テトラヒドロフラン、tert−ブチルメチルエーテル、酢酸エチル、アセトニトリルおよびN,N−ジメチルホルムアミドがより好ましい。これらの反応溶媒は単独または組み合わせて用いることができる。また、本発明の反応は無溶媒で行うこともできる。 Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated carbonization such as methylene chloride, chloroform and 1,2-dichloroethane. Hydrogen type, diethyl ether, tetrahydrofuran, diisopropyl ether, ether type such as tert-butyl methyl ether, ester type such as ethyl acetate and n-butyl acetate, nitrile type such as acetonitrile and propionitrile, N, N-dimethylformamide, Examples thereof include amides such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide. Among them, n-hexane, n-heptane, toluene, xylene, methylene chloride, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, ethyl acetate, acetonitrile, propionitrile, N, N-dimethylformamide and dimethyl sulfoxide are particularly preferable. More preferred are n-heptane, toluene, methylene chloride, tetrahydrofuran, tert-butyl methyl ether, ethyl acetate, acetonitrile and N, N-dimethylformamide. These reaction solvents can be used alone or in combination. In addition, the reaction of the present invention can be carried out without a solvent.
反応溶媒の使用量は、一般式[1]で示されるα−トリフルオロメチル−α−ヒドロキシエステル類1モルに対して0.01L(リットル)以上を用いれば良く、通常は0.03から30Lが好ましく、特に0.05から20Lがより好ましい。 The reaction solvent may be used in an amount of 0.01 L (liter) or more with respect to 1 mol of α-trifluoromethyl-α-hydroxyester represented by the general formula [1], and usually 0.03 to 30 L. In particular, 0.05 to 20 L is more preferable.
温度条件は、−30から+150℃の範囲で行えば良く、通常は−20から+140℃が好ましく、特に−10から+130℃がより好ましい。 The temperature condition may be in the range of −30 to + 150 ° C., usually −20 to + 140 ° C. is preferable, and −10 to + 130 ° C. is more preferable.
反応時間は、24時間以内の範囲で行えば良く、原料基質および反応条件により異なるため、ガスクロマトグラフィー、液体クロマトグラフィー、核磁気共鳴等の分析手段により反応の進行状況を追跡し、原料基質が殆ど消失した時点を終点とすることが好ましい。 The reaction time may be in the range of 24 hours or less, and varies depending on the raw material substrate and reaction conditions. Therefore, the progress of the reaction is traced by analysis means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, etc. The end point is preferably the point at which almost disappeared.
後処理は、反応終了液(必要に応じて反応溶媒を濃縮する)を有機溶媒(例えば、n−ヘキサン、n−ヘプタン、トルエン、キシレン、塩化メチレン、ジイソプロピルエーテル、tert−ブチルメチルエーテル、酢酸エチル等)で希釈し、水またはアルカリ金属の無機塩基(例えば、炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム等)の水溶液で洗浄し(必要に応じて無水硫酸ナトリウム、無水硫酸マグネシウム等の乾燥剤で乾燥する)、回収した有機層を濃縮することにより、一般式[2]で示されるα−トリフルオロメチル−α,β−不飽和エステル類を粗生成物として得ることができる。また、反応終了液から直接、減圧蒸留することにより粗生成物を得ることもでき、後処理操作が簡略化できる。粗生成物は、必要に応じて活性炭処理、蒸留、再結晶、カラムクロマトグラフィー等により、高い化学純度に精製することができる。一般式[2]で示されるα−トリフルオロメチル−α,β−不飽和エステル類の波線は、二重結合の立体化学がE体、Z体、またはE体とZ体の混合物であることを表し、得られる生成物の該立体化学は原料基質および反応条件により異なる。 In the post-treatment, the reaction completion solution (concentrate the reaction solvent as necessary) is used as an organic solvent (for example, n-hexane, n-heptane, toluene, xylene, methylene chloride, diisopropyl ether, tert-butyl methyl ether, ethyl acetate). Diluted with water or an aqueous solution of an alkali metal inorganic base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc.) (such as anhydrous sodium sulfate, anhydrous magnesium sulfate) The α-trifluoromethyl-α, β-unsaturated ester represented by the general formula [2] can be obtained as a crude product by concentrating the recovered organic layer. In addition, a crude product can be obtained by distillation under reduced pressure directly from the reaction end solution, and the post-treatment operation can be simplified. The crude product can be purified to a high chemical purity by activated carbon treatment, distillation, recrystallization, column chromatography or the like, if necessary. The wavy line of α-trifluoromethyl-α, β-unsaturated esters represented by the general formula [2] indicates that the stereochemistry of the double bond is E-form, Z-form, or a mixture of E-form and Z-form The stereochemistry of the resulting product varies depending on the raw material substrate and reaction conditions.
本発明においては、α−トリフルオロメチル−α−ヒドロキシエステル類を有機塩基の存在下にスルフリルフルオリドと反応させることにより、α−トリフルオロメチル−α,β−不飽和エステル類を製造することができる(態様1)。 In the present invention, α-trifluoromethyl-α, β-unsaturated esters are produced by reacting α-trifluoromethyl-α-hydroxyesters with sulfuryl fluoride in the presence of an organic base. (Aspect 1).
態様1の内、原料基質としては、β位置換基の片方が水素原子であり、他方がアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基であり、さらにエステル基がアルキルエステルである場合がより好ましい(態様2)。本態様の原料基質は入手が容易であり、所望の反応が良好に進行し、得られるα−トリフルオロメチル−α,β−不飽和エステル類も医農薬中間体として特に重要である。 In embodiment 1, as the raw material substrate, one of the β-position substituents is a hydrogen atom, and the other is an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group, More preferably, the ester group is an alkyl ester (Aspect 2). The raw material substrate of this embodiment is easily available, the desired reaction proceeds satisfactorily, and the α-trifluoromethyl-α, β-unsaturated esters obtained are particularly important as pharmaceutical and agrochemical intermediates.
態様1または態様2の内、有機塩基としては、1,5−ジアザビシクロ[4.3.0]ノン−5−エンまたは1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エンがより好ましい(態様3)。本態様の有機塩基を用いることにより、所望の反応がさらに良好に進行する。
[実施例]
実施例により本発明の実施の形態を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。
[実施例1]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
In Embodiment 1 or 2, the organic base is more preferably 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undec-7-ene. Preferred (Aspect 3). By using the organic base of this embodiment, the desired reaction proceeds even better.
[Example]
Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.
[Example 1]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類2.00g(10.75mmol、1.00eq)、アセトニトリル5.4mL(1.99M)とトリエチルアミン2.17g(21.44mmol、1.99eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)2.19g(21.46mmol、2.00eq)をボンベより吹き込み、室温で終夜攪拌した。反応終了液の19F−NMRより変換率は86%であった。変換率測定時の19F−NMRより、下記式 Α-trifluoromethyl-α-hydroxyesters represented by 2.00 g (10.75 mmol, 1.00 eq), 5.4 mL (1.99 M) of acetonitrile and 2.17 g (21.44 mmol, 1.99 eq) of triethylamine Was immersed in a refrigerant bath at −78 ° C., 2.19 g (21.46 mmol, 2.00 eq) of sulfuryl fluoride (SO 2 F 2 ) was blown from the bomb and stirred at room temperature overnight. The conversion rate was 86% from 19 F-NMR of the reaction completed liquid. From 19 F-NMR when measuring the conversion rate,
で示されるα−トリフルオロメチル−α,β−不飽和エステル類と、下記式 Α-trifluoromethyl-α, β-unsaturated esters represented by the formula:
で示されるフッ素化物の生成比は70:30であった。反応終了液の後処理は実施せず。1H−および19F−NMRを下に示す。
1H−NMR[基準物質;(CH3)4Si、重溶媒;CDCl3]、δ ppm;α−トリフルオロメチル−α,β−不飽和エステル類/1.35(t、7.1Hz、3H)、4.32(q、7.1Hz、2H)、6.42(s、1H)、6.72(s、1H)、フッ素化物/1.25−1.45(t、3H)、2.75−3.50(m、3H)、4.25−4.50(q、2H)。
19F−NMR(基準物質;C6F6、重溶媒;CDCl3)、δ ppm;α−トリフルオロメチル−α,β−不飽和エステル類/96.06(s、3F)、フッ素化物/31.88(s、1F)、83.73(s、3F)。
[実施例2]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
The production ratio of the fluorinated product represented by is 70:30. No post-treatment was performed on the reaction end solution. 1 H- and 19 F-NMR are shown below.
1 H-NMR [reference material; (CH 3 ) 4 Si, deuterated solvent; CDCl 3 ], δ ppm; α-trifluoromethyl-α, β-unsaturated esters / 1.35 (t, 7.1 Hz, 3H), 4.32 (q, 7.1 Hz, 2H), 6.42 (s, 1H), 6.72 (s, 1H), fluoride / 1.25-1.45 (t, 3H), 2.75-3.50 (m, 3H), 4.25-4.50 (q, 2H).
19 F-NMR (reference material; C 6 F 6 , heavy solvent; CDCl 3 ), δ ppm; α-trifluoromethyl-α, β-unsaturated esters / 96.06 (s, 3F), fluoride / 31.88 (s, 1F), 83.73 (s, 3F).
[Example 2]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類1.00g(4.38mmol、1.00eq)、アセトニトリル5.0mL(0.88M)とトリエチルアミン1.30g(12.85mmol、2.93eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)0.89g(8.72mmol、1.99eq)をボンベより吹き込み、室温で終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は92%であった。変換率測定時のガスクロマトグラフィー純度は80.7%{中間体[LG;脱離基(OSO2F)]10.1%、フッ素化物<5%}であり、E:Z比は40:60であった。反応終了液を酢酸エチル30mLで希釈し、飽和炭酸カリウム水溶液30mLで洗浄し、水30mLで洗浄し、無水硫酸マグネシウムで乾燥し、回収した有機層を減圧濃縮し、ショートカラムクロマトグラフィー(シリカゲル、酢酸エチル/n−ヘキサン系)で精製することにより、下記式 Α-trifluoromethyl-α-hydroxyesters represented by 1.00 g (4.38 mmol, 1.00 eq), 5.0 mL (0.88 M) of acetonitrile and 1.30 g (12.85 mmol, 2.93 eq) of triethylamine And immersed in a −78 ° C. refrigerant bath, 0.89 g (8.72 mmol, 1.99 eq) of sulfuryl fluoride (SO 2 F 2 ) was blown from the bomb and stirred at room temperature overnight. The conversion rate was 92% from the gas chromatography of the reaction completion liquid. The gas chromatography purity at the time of measuring the conversion rate was 80.7% {intermediate [LG; leaving group (OSO 2 F)] 10.1%, fluorinated compound <5%}, and the E: Z ratio was 40: 60. The reaction-terminated liquid is diluted with 30 mL of ethyl acetate, washed with 30 mL of saturated aqueous potassium carbonate solution, washed with 30 mL of water, dried over anhydrous magnesium sulfate, and the collected organic layer is concentrated under reduced pressure and subjected to short column chromatography (silica gel, acetic acid). (Ethyl / n-hexane system)
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の精製品を0.63g得た。収率は68%であった。ガスクロマトグラフィー純度は74.7%であり、E:Z比は34:66であった。1H−および19F−NMRを下に示す。
1H−NMR[基準物質;(CH3)4Si、重溶媒;CDCl3]、δ ppm;E体/1.05−1.15(d、6H)、1.25−1.40(t、3H)、3.29(m、1H)、4.20−4.35(q、2H)、6.56(d、10.2Hz、1H)、Z体/1.05−1.15(d、6H)、1.25−1.40(t、3H)、3.08(m、1H)、4.20−4.35(q、2H)、6.97(d、11.0Hz、1H)。
19F−NMR(基準物質;C6F6、重溶媒;CDCl3)、δ ppm;E体/97.80(s、3F)、Z体/103.05(s、3F)。
[実施例3]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
As a result, 0.63 g of a purified product of α-trifluoromethyl-α, β-unsaturated ester represented by the formula (1) was obtained. The yield was 68%. The gas chromatography purity was 74.7% and the E: Z ratio was 34:66. 1 H- and 19 F-NMR are shown below.
1 H-NMR [reference substance; (CH 3 ) 4 Si, deuterated solvent; CDCl 3 ], δ ppm; E-form / 1.05-1.15 (d, 6H), 1.25-1.40 (t 3H), 3.29 (m, 1H), 4.20-4.35 (q, 2H), 6.56 (d, 10.2 Hz, 1H), Z-form / 1.05-1.15 ( d, 6H), 1.25-1.40 (t, 3H), 3.08 (m, 1H), 4.20-4.35 (q, 2H), 6.97 (d, 11.0 Hz, 1H).
19 F-NMR (reference substance; C 6 F 6 , heavy solvent; CDCl 3 ), δ ppm; E-form / 97.80 (s, 3F), Z-form / 103.05 (s, 3F).
[Example 3]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類1.00g(4.38mmol、1.00eq)、アセトニトリル5.0mL(0.88M)と1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)1.97g(12.94mmol、2.95eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)0.90g(8.82mmol、2.01eq)をボンベより吹き込み、50℃で終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は100%であった。変換率測定時のガスクロマトグラフィー純度(DBUのピークを除いて補正)は96.9%{中間体[LG;脱離基(OSO2F)]1.2%、フッ素化物<5%}であり、E:Z比は37:63であった。反応終了液を酢酸エチル30mLで希釈し、飽和炭酸カリウム水溶液30mLで洗浄し、水30mLで洗浄し、無水硫酸マグネシウムで乾燥し、回収した有機層を減圧濃縮し、ショートカラムクロマトグラフィー(シリカゲル、酢酸エチル/n−ヘキサン系)で精製することにより、下記式 1.00g (4.38mmol, 1.00eq), 5.0mL (0.88M) of acetonitrile and 1,8-diazabicyclo [5.4.0] undece 1.97 g (12.94 mmol, 2.95 eq) of −7-ene (DBU) was added and immersed in a −78 ° C. refrigerant bath, 0.90 g (8.82 mmol, 2.82 mmol, sulfuryl fluoride (SO 2 F 2 )). 01 eq) was blown from a cylinder and stirred at 50 ° C. overnight. The conversion rate was 100% from the gas chromatography of the reaction completed liquid. Gas chromatographic purity (corrected excluding DBU peak) at the time of measuring the conversion rate was 96.9% {intermediate [LG; leaving group (OSO 2 F)] 1.2%, fluoride <5%}. Yes, the E: Z ratio was 37:63. The reaction-terminated liquid is diluted with 30 mL of ethyl acetate, washed with 30 mL of saturated aqueous potassium carbonate solution, washed with 30 mL of water, dried over anhydrous magnesium sulfate, and the collected organic layer is concentrated under reduced pressure and subjected to short column chromatography (silica gel, acetic acid). (Ethyl / n-hexane system)
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の精製品を0.74g得た。収率は80%であった。ガスクロマトグラフィー純度は98.4%であり、E:Z比は42:58であった。1H−および19F−NMRは実施例2と同等であった。
[実施例4]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
0.74 g of a purified product of α-trifluoromethyl-α, β-unsaturated ester represented by The yield was 80%. The gas chromatography purity was 98.4% and the E: Z ratio was 42:58. 1 H- and 19 F-NMR were equivalent to Example 2.
[Example 4]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類2.00g(7.63mmol、1.00eq)、アセトニトリル10.0mL(0.76M)と1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)3.48g(22.86mmol、3.00eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)1.56g(15.29mmol、2.00eq)をボンベより吹き込み、50℃で終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は95%であった。変換率測定時のガスクロマトグラフィー純度(DBUと原料基質由来不純物のピークを除いて補正)は90.6%(フッ素化物<5%)であり、E:Z比は90:10であった。反応終了液を酢酸エチル30mLで希釈し、飽和炭酸カリウム水溶液30mLで洗浄し、水30mLで洗浄し、無水硫酸マグネシウムで乾燥し、回収した有機層を減圧濃縮し、ショートカラムクロマトグラフィー(シリカゲル、酢酸エチル/n−ヘキサン系)で精製することにより、下記式 2.00 g (7.63 mmol, 1.00 eq), 10.0 mL (0.76 M) of acetonitrile and 1,8-diazabicyclo [5.4.0] undece 3.48 g (22.86 mmol, 3.00 eq) of −7-ene (DBU) was added and immersed in a −78 ° C. refrigerant bath to give 1.56 g (15.29 mmol, 2.29 mmol, sulfuryl fluoride (SO 2 F 2 )). 00eq) was blown from a cylinder and stirred at 50 ° C. overnight. The conversion was 95% by gas chromatography of the reaction completed liquid. The gas chromatographic purity (corrected excluding the peaks of DBU and raw material substrate-derived impurities) at the time of conversion rate measurement was 90.6% (fluoride <5%), and the E: Z ratio was 90:10. The reaction-terminated liquid is diluted with 30 mL of ethyl acetate, washed with 30 mL of saturated aqueous potassium carbonate solution, washed with 30 mL of water, dried over anhydrous magnesium sulfate, and the collected organic layer is concentrated under reduced pressure and subjected to short column chromatography (silica gel, acetic acid). (Ethyl / n-hexane system)
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の精製品を1.69g得た。収率は91%であった。ガスクロマトグラフィー純度(原料基質由来不純物のピークを除いて補正)は90.5%であり、E:Z比は87:13であった。1H−および19F−NMRを下に示す。
1H−NMR[基準物質;(CH3)4Si、重溶媒;CDCl3]、δ ppm;E体/1.20(t、7.2Hz、3H)、4.26(q、7.2Hz、2H)、7.15−7.45(Ar−H、5H + s、1H)、Z体/1.15−1.45(t、3H)、4.05−4.45(q、2H)、7.15−7.45(Ar−H、5H)、8.09(s、1H)。
19F−NMR(基準物質;C6F6、重溶媒;CDCl3)、δ ppm;E体/97.85(s、3F)、Z体/103.81(s、3F)。
[実施例5]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
1.69 g of a purified product of α-trifluoromethyl-α, β-unsaturated ester represented by the formula (1) was obtained. The yield was 91%. The gas chromatographic purity (corrected excluding the peaks of impurities derived from the raw material substrate) was 90.5%, and the E: Z ratio was 87:13. 1 H- and 19 F-NMR are shown below.
1 H-NMR [reference material; (CH 3 ) 4 Si, heavy solvent; CDCl 3 ], δ ppm; E-form / 1.20 (t, 7.2 Hz, 3 H), 4.26 (q, 7.2 Hz) 2H), 7.15-7.45 (Ar-H, 5H + s, 1H), Z-form / 1.15-1.45 (t, 3H), 4.05-4.45 (q, 2H) ), 7.15-7.45 (Ar-H, 5H), 8.09 (s, 1H).
19 F-NMR (reference substance; C 6 F 6 , heavy solvent; CDCl 3 ), δ ppm; E-form / 97.85 (s, 3F), Z-form / 103.81 (s, 3F).
[Example 5]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類1.00g(3.81mmol、1.00eq)、アセトニトリル5.0mL(0.76M)、1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)0.29g(1.90mmol、0.50eq)とトリエチルアミン0.77g(7.61mmol、2.00eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)0.78g(7.64mmol、2.01eq)をボンベより吹き込み、50℃で終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は95%であった。変換率測定時のガスクロマトグラフィー純度(DBUと原料基質由来不純物のピークを除いて補正)は80.2%(フッ素化物<5%)であり、E:Z比は90:10であった。反応終了液を酢酸エチル20mLで希釈し、飽和炭酸カリウム水溶液20mLで洗浄し、水20mLで洗浄し、無水硫酸ナトリウムで乾燥し、回収した有機層を減圧濃縮し、真空乾燥することにより、下記式 Α-trifluoromethyl-α-hydroxyesters represented by the formula: 1.00 g (3.81 mmol, 1.00 eq), acetonitrile 5.0 mL (0.76 M), 1,8-diazabicyclo [5.4.0] undece -7-ene (DBU) (0.29 g, 1.90 mmol, 0.50 eq) and triethylamine (0.77 g, 7.61 mmol, 2.00 eq) were added, immersed in a refrigerant bath at -78 ° C, and sulfuryl fluoride (SO 2 F 2 ) 0.78 g (7.64 mmol, 2.01 eq) was blown from the bomb and stirred at 50 ° C. overnight. The conversion was 95% by gas chromatography of the reaction completed liquid. The gas chromatographic purity (corrected excluding the peaks of DBU and impurities derived from the raw material substrate) at the time of measuring the conversion rate was 80.2% (fluoride <5%), and the E: Z ratio was 90:10. The reaction-terminated liquid is diluted with 20 mL of ethyl acetate, washed with 20 mL of saturated aqueous potassium carbonate solution, washed with 20 mL of water, dried over anhydrous sodium sulfate, and the collected organic layer is concentrated under reduced pressure and dried under vacuum to obtain the following formula.
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の粗生成物を0.92g得た。収率は99%であった。ガスクロマトグラフィー純度(原料基質由来不純物のピークを除いて補正)は83.6%であり、E:Z比は75:25であった。1H−および19F−NMRは実施例4と同等であった。
[実施例6]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
0.92 g of a crude product of α-trifluoromethyl-α, β-unsaturated ester represented by the formula (1) was obtained. The yield was 99%. The gas chromatographic purity (corrected excluding the peaks of impurities derived from the raw material substrate) was 83.6%, and the E: Z ratio was 75:25. 1 H- and 19 F-NMR were equivalent to Example 4.
[Example 6]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類3.00g(13.26mmol、1.00eq)、アセトニトリル10.0mL(1.33M)、1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)1.00g(6.57mmol、0.50eq)とトリエチルアミン2.68g(26.48mmol、2.00eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)4.06g(39.78mmol、3.00eq)をボンベより吹き込み、50℃で終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は100%であった。変換率測定時のガスクロマトグラフィー純度は96.1%(フッ素化物<5%)であり、E:Z比は92:8であった。反応終了液を酢酸エチル30mLで希釈し、飽和炭酸カリウム水溶液30mLで洗浄し、水30mLで2回洗浄し、無水硫酸マグネシウムで乾燥し、回収した有機層を減圧濃縮し、真空乾燥することにより、下記式 Α-trifluoromethyl-α-hydroxyesters represented by the formula: 3.00 g (13.26 mmol, 1.00 eq), acetonitrile 10.0 mL (1.33 M), 1,8-diazabicyclo [5.4.0] undece Add 1.00 g (6.57 mmol, 0.50 eq) of -7-ene (DBU) and 2.68 g (26.48 mmol, 2.00 eq) of triethylamine, soak it in a refrigerant bath at -78 ° C, and add sulfuryl fluoride (SO 2 F 2 ) (4.06 g, 39.78 mmol, 3.00 eq) was blown from the bomb and stirred at 50 ° C. overnight. The conversion rate was 100% from the gas chromatography of the reaction completed liquid. The gas chromatography purity at the time of measuring the conversion rate was 96.1% (fluorinated product <5%), and the E: Z ratio was 92: 8. The reaction-terminated liquid was diluted with 30 mL of ethyl acetate, washed with 30 mL of saturated aqueous potassium carbonate solution, washed twice with 30 mL of water, dried over anhydrous magnesium sulfate, and the collected organic layer was concentrated under reduced pressure and dried under vacuum. Following formula
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の粗生成物を2.62g得た。収率は95%であった。ガスクロマトグラフィー純度は97.9%であり、E:Z比は92:8であった。1H−および19F−NMRを下に示す。
1H−NMR[基準物質;(CH3)4Si、重溶媒;CDCl3]、δ ppm;E体/1.33(t、7.2Hz、3H)、1.90(s、3H)、4.30(q、7.2Hz、2H)、5.31(s、1H)、5.33(s、1H)、6.83(s、1H)、Z体/1.33(t、7.2Hz、3H)、1.93(s、3H)、4.30(q、7.2Hz、2H)、5.11(s、1H)、5.21(s、1H)、7.50(s、1H)。
19F−NMR(基準物質;C6F6、重溶媒;CDCl3)、δ ppm;E体/98.05(s、3F)、Z体/103.85(s、3F)。
[実施例7]
ステンレス鋼(SUS)製耐圧反応容器に、下記式
As a result, 2.62 g of a crude product of α-trifluoromethyl-α, β-unsaturated ester represented by formula (1) was obtained. The yield was 95%. The gas chromatography purity was 97.9% and the E: Z ratio was 92: 8. 1 H- and 19 F-NMR are shown below.
1 H-NMR [reference material; (CH 3 ) 4 Si, deuterated solvent; CDCl 3 ], δ ppm; E-form / 1.33 (t, 7.2 Hz, 3 H), 1.90 (s, 3 H), 4.30 (q, 7.2 Hz, 2H), 5.31 (s, 1H), 5.33 (s, 1H), 6.83 (s, 1H), Z-form / 1.33 (t, 7 .2 Hz, 3 H), 1.93 (s, 3 H), 4.30 (q, 7.2 Hz, 2 H), 5.11 (s, 1 H), 5.21 (s, 1 H), 7.50 ( s, 1H).
19 F-NMR (reference substance; C 6 F 6 , heavy solvent; CDCl 3 ), δ ppm; E-form / 98.05 (s, 3F), Z-form / 103.85 (s, 3F).
[Example 7]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類50.00g(249.80mmol、1.00eq)、アセトニトリル83.0mL(3.01M)、1,8−ジアザビシクロ[5.4.0]ウンデセ−7−エン(DBU)19.00g(124.80mmol、0.50eq)とトリエチルアミン63.20g(624.57mmol、2.50eq)を加え、−78℃の冷媒浴に浸し、スルフリルフルオリド(SO2F2)51.00g(499.71mmol、2.00eq)をボンベより吹き込み、室温で終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は99%であった。変換率測定時のガスクロマトグラフィー純度は82.1%(フッ素化物9.0%)であり、E:Z比は78:22であった。反応終了液を直接、減圧蒸留(沸点52〜58℃/減圧度5000Pa)することにより、下記式 50.00 g (249.80 mmol, 1.00 eq), 83.0 mL (3.01 M) of acetonitrile, 1,8-diazabicyclo [5.4.0] undece 19.00 g (124.80 mmol, 0.50 eq) of −7-ene (DBU) and 63.20 g (624.57 mmol, 2.50 eq) of triethylamine were added, immersed in a refrigerant bath at −78 ° C., and sulfuryl fluoride (SO 2). 2 F 2 ) 51.00 g (499.71 mmol, 2.00 eq) was blown from the bomb and stirred at room temperature overnight. The conversion was 99% by gas chromatography of the reaction completed liquid. The gas chromatography purity at the time of measuring the conversion rate was 82.1% (fluoride 9.0%), and the E: Z ratio was 78:22. By directly distilling the reaction end solution under reduced pressure (boiling point 52-58 ° C./decompression degree 5000 Pa),
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の粗生成物を17.21g得た。収率は38%であった。ガスクロマトグラフィー純度は82.8%(フッ素化物10.5%)であり、E:Z比は79:21であった。1H−および19F−NMRを下に示す。
1H−NMR[基準物質;(CH3)4Si、重溶媒;CDCl3]、δ ppm;E体/1.34(t、7.2Hz、3H)、2.17(dq、7.3Hz、2.2Hz、3H)、4.31(q、7.2Hz、2H)、6.95(q、7.3Hz、1H)、Z体/1.25−1.40(t、3H)、2.09(dq、7.6Hz、2.8Hz、3H)、4.20−4.45(q、2H)、7.33(q、7.6Hz、1H)。
19F−NMR(基準物質;C6F6、重溶媒;CDCl3)、δ ppm;E体/97.64(s、3F)、Z体/103.00(s、3F)。
17.21 g of a crude product of α-trifluoromethyl-α, β-unsaturated ester represented by the formula (1) was obtained. The yield was 38%. The gas chromatography purity was 82.8% (fluoride 10.5%), and the E: Z ratio was 79:21. 1 H- and 19 F-NMR are shown below.
1 H-NMR [reference substance; (CH 3 ) 4 Si, deuterated solvent; CDCl 3 ], δ ppm; E-form / 1.34 (t, 7.2 Hz, 3 H), 2.17 (dq, 7.3 Hz) , 2.2 Hz, 3 H), 4.31 (q, 7.2 Hz, 2 H), 6.95 (q, 7.3 Hz, 1 H), Z body / 1.25-1.40 (t, 3 H), 2.09 (dq, 7.6 Hz, 2.8 Hz, 3H), 4.20-4.45 (q, 2H), 7.33 (q, 7.6 Hz, 1H).
19 F-NMR (reference material; C 6 F 6 , heavy solvent; CDCl 3 ), δ ppm; E-form / 97.64 (s, 3F), Z-form / 103.00 (s, 3F).
下記式 Following formula
で示されるフッ素化物の1H−および19F−NMRを下に示す。
1H−NMR[基準物質;(CH3)4Si、重溶媒;CDCl3]、δ ppm;1.25−1.40(t、3H + m、3H)、3.65−3.85(m、1H)、3.85−4.00(m、1H)、4.20−4.45(q、2H)。
19F−NMR(基準物質;C6F6、重溶媒;CDCl3)、δ ppm;30.08(s、1F)、80.39(s、3F)。
[比較例1]
下記式
1 H- and 19 F-NMR of the fluorinated compound represented by the formula is shown below.
1 H-NMR [reference material; (CH 3 ) 4 Si, deuterated solvent; CDCl 3 ], δ ppm; 1.25 to 1.40 (t, 3H + m, 3H), 3.65 to 3.85 ( m, 1H), 3.85-4.00 (m, 1H), 4.20-4.45 (q, 2H).
19 F-NMR (reference material; C 6 F 6 , heavy solvent; CDCl 3 ), δ ppm; 30.08 (s, 1F), 80.39 (s, 3F).
[Comparative Example 1]
Following formula
で示されるα−トリフルオロメチル−α−ヒドロキシエステル類0.30g(1.31mmol、1.00eq)の塩化メチレン溶液(使用量5.0mL、0.26M)に、氷冷下でトリフルオロメタンスルホン酸無水物[(CF3SO2)2O]0.58g(2.06mmol、1.57eq)を加え、10分間攪拌した。同温度でピリジン0.26g(3.29mmol、2.51eq)を加え、1時間攪拌した。さらに室温まで昇温し、終夜攪拌した。反応終了液のガスクロマトグラフィーより変換率は86%であった。変換率測定時のガスクロマトグラフィーより、下記式 To a methylene chloride solution (amount used: 5.0 mL, 0.26 M) of 0.30 g (1.31 mmol, 1.00 eq) of α-trifluoromethyl-α-hydroxyester represented by the formula below was added trifluoromethanesulfone under ice-cooling. 0.58 g (2.06 mmol, 1.57 eq) of acid anhydride [(CF 3 SO 2 ) 2 O] was added and stirred for 10 minutes. At the same temperature, 0.26 g (3.29 mmol, 2.51 eq) of pyridine was added and stirred for 1 hour. The mixture was further warmed to room temperature and stirred overnight. The conversion was 86% by gas chromatography of the reaction completed liquid. From gas chromatography at the time of conversion rate measurement,
で示されるα−トリフルオロメチル−α,β−不飽和エステル類の純度は0.7%{中間体[LG;脱離基(OSO2CF3)]83.8%}であり、E:Z比は60:40であった。反応終了液の後処理は実施せず。 The purity of the α-trifluoromethyl-α, β-unsaturated ester represented by the formula is 0.7% {intermediate [LG; leaving group (OSO 2 CF 3 )] 83.8%}, and E: The Z ratio was 60:40. No post-treatment was performed on the reaction end solution.
比較例2は、実施例2を参考にして反応剤を換えて同様に実施した。比較例3は、実施例3を参考にして反応剤を換えて同様に実施した。比較例4は、比較例1を参考にして原料基質を換えて同様に実施した。 Comparative Example 2 was carried out in the same manner with reference to Example 2 with the reactants changed. Comparative Example 3 was carried out in the same manner with reference to Example 3 with the reactants changed. Comparative Example 4 was carried out in the same manner with reference to Comparative Example 1 except that the raw material substrate was changed.
Claims (3)
[式中、R1およびR2はそれぞれ独立に水素原子、アルキル基、置換アルキル基、アルケニル基、置換アルケニル基、アルキニル基、置換アルキニル基、芳香環基、置換芳香環基、アルキルカルボニル基、置換アルキルカルボニル基、アルコキシカルボニル基、置換アルコキシカルボニル基、アリールカルボニル基、置換アリールカルボニル基、シアノ基またはニトロ基を表し、R3はアルキル基または置換アルキル基を表す。一般式[2]の波線は、二重結合の立体化学がE体、Z体、またはE体とZ体の混合物であることを表す] General formula [1]
Wherein R 1 and R 2 are each independently a hydrogen atom, alkyl group, substituted alkyl group, alkenyl group, substituted alkenyl group, alkynyl group, substituted alkynyl group, aromatic ring group, substituted aromatic ring group, alkylcarbonyl group, A substituted alkylcarbonyl group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an arylcarbonyl group, a substituted arylcarbonyl group, a cyano group or a nitro group is represented, and R 3 represents an alkyl group or a substituted alkyl group. The wavy line of general formula [2] indicates that the stereochemistry of the double bond is E-form, Z-form, or a mixture of E-form and Z-form]
[式中、R4はアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基を表し、R5はアルキル基を表す。一般式[4]の波線は、二重結合の立体化学がE体、Z体、またはE体とZ体の混合物であることを表す] General formula [3]
[Wherein, R 4 represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group, and R 5 represents an alkyl group. The wavy line in the general formula [4] indicates that the stereochemistry of the double bond is E-form, Z-form, or a mixture of E-form and Z-form]
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